Cytology of Rhytidhysteron rufulum: An emerging cause of phaeohyphomycosis.

Fine-needle aspiration cytology (FNAC) is often the first-line investigation for detection of any fungal infection. Rhytidhysteron rufulum is an emerging dematiaceous fungus detected as a human pathogen. FNAC combined with molecular techniques helps in the detection of rare fungal species, especially in cases of non-sporulating fungi. We describe the cytomorphologic features of this species in a 62-year immunocompetent male who presented with a localised subcutaneous infection. Molecular studies helped in the final diagnosis.

Combination therapy with itraconazole and terbinafine for phaeohyphomycosis caused by Exophiala spinifera: A case report and literature review.

Exophiala spinifera is a rare dematiaceous fungus causing cutaneous, subcutaneous and disseminated phaeohyphomycosis (PHM). Standard antifungal therapy for PHM is still uncertain. Here, we report a case of a Chinese male with PHM caused by E. spinifera, who received significant clinical improvement after the treatment with oral itraconazole and terbinafine. With the aim of evaluating the antifungal therapy for PHM caused by E. spinifera, a detailed review was performed.

Subcutaneous phaeohyphomycosis caused by Alternaria section Alternaria.

A woman presented with purulent infiltrating plaques on her hands and arms after a 7-year history of nephrotic syndrome. She was ultimately diagnosed with subcutaneous phaeohyphomycosis, which is caused by Alternaria section Alternaria. The lesions completely resolved after 2 months of antifungal treatment. Interestingly, spores (round-shaped cells) and hyphae were observed in the biopsy and pus specimens, respectively. This case report highlights that distinguishing subcutaneous phaeohyphomycosis from chromoblastomycosis may be difficult if the diagnosis is solely based on pathological findings. It also emphasizes that the parasitic forms of the dematiaceous fungi in immunosuppressed hosts may vary with the site and environment.

Clinical characteristics of central nervous system phaeohyphomycosis: A brief report of 20 years' experience.

Central nervous system (CNS) phaeohyphomycosis is a rare and often fatal fungal infection. Our study reported a case series of eight CNS phaeohyphomycosis cases at our institution over the past 20 years. We did not observe the common pattern of risk factors, abscess location, or number of abscesses among them. Most patients were immunocompetent without classic risk factors for fungal infection. Early diagnosis and aggressive management with surgical intervention and prolonged antifungal therapy can lead to a favorable outcome. The study highlights the need for further research to better understand the pathogenesis and optimal management of this challenging rare infection.

Mouse Models of Phaeohyphomycosis.

Infections by dematiaceous fungi especially phaeohyphomycosis are an emerging group of infectious diseases worldwide with a variety of clinical presentations. The mouse model is a useful tool for studying phaeohyphomycosis, which can mimic dematiaceous fungal infections in humans. Our laboratory has successfully constructed a mouse model of subcutaneous phaeohyphomycosis and found significant phenotypic differences between Card9 knockout and wild-type mice, mirroring the increased susceptibility to this infection observed in CARD9-deficient humans. Here we describe construction of the mouse model of subcutaneous phaeohyphomycosis and related experiments. We hope that this chapter can be beneficial for the study of phaeohyphomycosis and facilitate the development of new diagnostic and therapeutic approaches.

Pulmonary phaeohyphomycosis due to Exophiala dermatitidis in a patient with pulmonary non-tuberculous mycobacterial infection.

A 65-year-old Japanese woman repeatedly withdrew and resumed antibiotics against pulmonary non-tuberculous mycobacterial infection caused by Mycobacterium intracellulare for more than 10 years. Although she continued to take medications, her respiratory symptoms and chest computed tomography indicated an enlarged infiltrative shadow in the lingular segment of the left lung that gradually worsened over the course of a year or more. Bronchoscopy was performed and mycobacterial culture of the bronchial lavage fluid was negative, whereas Exophiala dermatitidis was detected. After administration of oral voriconazole was initiated, the productive cough and infiltrative shadow resolved. There are no characteristic physical or imaging findings of E. dermatitidis, and it often mimics other chronic respiratory infections. Thus, when confronting refractory non-tuberculous mycobacterial cases, it might be better to assume other pathogenic microorganisms, including E. dermatitidis, and actively perform bronchoscopy.

Disseminated Medicopsis romeroi infection in a kidney transplant recipient: A case report.

Medicopsis romeroi is a rare, dematiaceous fungus that is difficult to identify using conventional fungal tests. Although uncommon, immunocompromised patients are particularly susceptible to this opportunistic fungus. Here, we report the case of a renal transplant recipient who presented with painful disseminated subcutaneous and soft tissue lesions. Sequencing of the Internal transcribed spacer (ITS) region of the ribosomal DNA identified the fungus as Medicopsis romeroi. Additionally, tissue samples from a non-healing wound on the left forearm grew Rhizopus spp. on Sabouraud dextrose agar, indicating a Mucormycosis superinfection. The patient's condition improved with surgical intervention and antifungal therapy with Posaconazole and Terbinafine. This case demonstrates the need for a high index of suspicion in order to facilitate early diagnosis and treatment and thus reduce the risk of dissemination.

Primary Intraventricular Phaeohyphomycosis: An Atypical Presentation of Neurotropic Fungus.

Cerebral fungal infections are usually reported secondary to contiguous spread from paranasal sinuses or orbit, hematogenous spread, traumatic brain injury, or immunocompromised conditions. Primary isolated intraventricular phaeohyphomycosis is rare. We report a 29-year-old man who presented with acute symptomatic unilateral hydrocephalus with an intraventricular lesion. Intraventricular endoscopy demonstrated 3 lesions along the choroid plexus with turbid cerebrospinal fluid. The lesions were yellowish in appearance. Excision of all lesions was done along with septostomy. The histopathology of the lesion as well as cerebrospinal fluid showed thin, septate, pigmented hyphae suggestive of phaeohyphomycosis. The patient initially responded to oral voriconazole but later developed acute symptoms and died 3 months after surgery despite continuous antifungal treatment. Primary intraventricular phaeohyphomycosis is uncommon and may have a dismal prognosis even with early diagnosis and prompt treatment.

Subcutaneous Phaeohyphomycosis in a Renal Transplant Patient by a Rare Fungus Medicopsis romeroi.

Medicopsis romeroi is a dematiaceous fungus that rarely causes subcutaneous phaeohyphomycosis. Here, we report a subcutaneous phaeohyphomycosis caused by a rare dematiaceous fungus, M. romeroi, in a 56-year-old male renal transplant patient. The patient was admitted for graft dysfunction and was found to have painless swelling over the anterior aspect of the right knee, which was aspirated twice within 40 days. Broad septate hyphae (determined by microscopy) and growth of phaeoid in a culture were observed in both the specimens. No sporulation was observed in the slide culture. Swelling recurred even after treatment with voriconazole, so the lesion was surgically excised. Genotypically, the isolate was identified as M. romeroi in both specimens. He was discharged on voriconazole. During a 6-month follow-up, no relapse was noticed. Phaeohyphomycosis caused by M. romeroi is rare, with only a few cases reported in India. Laboratory diagnosis of Medicopsis by conventional methods is challenging. Medicopsis species should be considered one of the etiological agents for subcutaneous phaeohyphomycosis. Molecular methods should be used for the identification of unusual pathogens.

Phaeohyphomycosis caused by Neoscytalidiumdimidiatum in a COVID-19 patient.

BACKGROUND: Neoscytalidiumdimidiatum is an opportunistic dematiaceous fungus belonging to the class Dothideomycetes. CASE REPORT: We report a case of N. dimidiatum cerebral phaeohyphomycosis post COVID-19 infection in a 32-year-old male from Iran. The causative agent was identified by cytopathology, routine mycological methods, and DNA sequencing of the internal transcribed spacer (ITS) region of rDNA. Apart from COVID-19 complications and the corticosteroid therapy, no underlying condition was diagnosed. The symptoms suggesting the fungal infection were shown two weeks after being discharged from COVID-19 hospital stay. Magnetic resonance of the brain showed a multi-focal central nervous system infection. The delayed identification of the fungus and, thus, a late starting of the antifungal treatment with amphotericin B, might have affected the patient outcome as he finally died. CONCLUSIONS: Considering the rare incidence of N. dimidiatum infections, this case should aware us about them, leading to a timely antifungal management.

Human Dectin-1 deficiency impairs macrophage-mediated defense against phaeohyphomycosis.

Subcutaneous phaeohyphomycosis typically affects immunocompetent individuals following traumatic inoculation. Severe or disseminated infection can occur in CARD9 deficiency or after transplantation, but the mechanisms protecting against phaeohyphomycosis remain unclear. We evaluated a patient with progressive, refractory Corynespora cassiicola phaeohyphomycosis and found that he carried biallelic deleterious mutations in CLEC7A encoding the CARD9-coupled, ß-glucan-binding receptor, Dectin-1. The patient's PBMCs failed to produce TNF-α and IL-1ß in response to ß-glucan and/or C. cassiicola. To confirm the cellular and molecular requirements for immunity against C. cassiicola, we developed a mouse model of this infection. Mouse macrophages required Dectin-1 and CARD9 for IL-1ß and TNF-α production, which enhanced fungal killing in an interdependent manner. Deficiency of either Dectin-1 or CARD9 was associated with more severe fungal disease, recapitulating the human observation. Because these data implicated impaired Dectin-1 responses in susceptibility to phaeohyphomycosis, we evaluated 17 additional unrelated patients with severe forms of the infection. We found that 12 out of 17 carried deleterious CLEC7A mutations associated with an altered Dectin-1 extracellular C-terminal domain and impaired Dectin-1-dependent cytokine production. Thus, we show that Dectin-1 and CARD9 promote protective TNF-α- and IL-1ß-mediated macrophage defense against C. cassiicola. More broadly, we demonstrate that human Dectin-1 deficiency may contribute to susceptibility to severe phaeohyphomycosis by certain dematiaceous fungi.

The Pedal Subcutaneous Phaeohyphomycotic Cyst in an Immunocompetent Adult Man: A Case Report.

Phaeohyphomycosis is a spectrum of subcutaneous and systemic infections caused by a variety of dematiaceous fungi. It is an opportunistic disease with an increased incidence in immunocompromised patients. We report a case of a pedal phaeohyphomycotic cyst in an immunocompetent adult male immigrant with the goal of highlighting its clinical presentation, diagnosis, and optimal treatment. A 57-year-old male immigrant from Panama presented with a painless, gradually increasing, large cystic lesion in his left foot, first intermetatarsal space, which had been present for many years. The patient was treated with surgical excision without antifungal therapy. Histologic analysis showed multiple granulomas composed of fibrin and necrosis in the centers surrounded by proliferative palisading fibroblasts admixed with heavily infiltrated neutrophils, plasma cells, macrophages, lymphocytes, and eosinophils. Periodic acid-Schiff and Fontana-Masson stains revealed sporadic, scattered dematiaceous fungal hyphae and pseudohyphae among granulomatous tissues. The mass was diagnosed as a phaeohyphomycotic cyst. Polymerase chain reaction-based sequencing failed to identify the fungal species because of the rarity of the fungal elements in the granulomatous tissues. The patient had no recurrence at a follow-up of 2 years. A phaeohyphomycotic cyst is a rare entity that needs to be differentiated from other benign and malignant lesions. Multiple modalities, including clinical evaluation, radiography, histologic analysis, microbiological culture, and nucleic acid sequencing, should be used for the final diagnosis. Surgical excision is an optimal treatment. Antifungal therapy should be considered based on the patient's clinical manifestation, surgical excision, and immune functional status.

Management of Extensive Central Nervous System Cladophialophora bantiana Infection in a 9-Year-Old Child.

BACKGROUND: Pediatric central nervous system (CNS) phaeohyphomycosis is a rare invasive fungal infection associated with high mortality. METHODS: We describe a child with progressive neurologic symptoms whose ultimate diagnosis was Cladophialophora bantiana -associated CNS phaeohyphomycosis. We discuss her clinical presentation, medical and surgical management and review the current literature. RESULTS: A 9-year-old female presented with acute onset of headaches, ophthalmoplegia and ataxia. Initial infectious work-up was negative, including serial fungal cerebrospinal fluid cultures. Over 2 months, she experienced progressive cognitive and motor declines, and imaging revealed worsening meningitis, ventriculitis and cerebritis. Ultimately, Cladophialophora was detected by plasma metagenomic next-generation sequencing (mNGS). Fourth ventricle fluid sampling confirmed the diagnosis of C. bantiana infection. Given the extent of her disease, complete surgical resection was not feasible. She required multiple surgical debridement procedures and prolonged antifungal therapy, including the instillation of intraventricular amphotericin B. With aggressive surgical and medical management, despite her continued neurologic deficits, she remains alive 3 years after her initial diagnosis. To our knowledge, this is one of a few published pediatric cases of CNS phaeohyphomycosis and the first with the causative pathogen identified by plasma mNGS. CONCLUSION: CNS phaeohyphomycosis is a serious, life-threatening infection. The preferred management includes a combination of surgical resection and antifungal therapy. In cases complicated by refractory ventriculitis, intraventricular antifungal therapy can be considered as adjuvant therapy. Direct sampling of the CNS for pathogen identification and susceptibility testing is the gold standard for diagnosis; however, the use of plasma mNGS may expedite the diagnosis.

CARD9 deficiency predisposing chromoblastomycosis: A case report and comparative transcriptome study.

CARD9 mutations are known to predispose patients to phaeohyphomycosis caused by different dematiaceous fungal species. In this study, we report for the first time a patient of chromoblastomycosis caused by Phialophora expanda, who harbored CARD9 mutation. Through a series of in vivo and in vitro studies, especially a comparative transcriptome study, we compared this case with our former patient suffering from phaeohyphomycosis caused by Phialophora americana. We showed that P. expanda is prone to forming sclerotic bodies both in vitro and in Card9 knockout mice, and has a stronger immunogenicity than P. americana. These data preliminary demonstrated that besides host defense, fungal specificity also contributed to the clinical phenotype in CARD9 deficient patients with dematiaceous fungal infections.

Cutaneous Phaeohyphomycosis of the Right Hand Caused by Exophiala jeanselmei: A Case Report and Literature Review.

Exophiala spp. is increasingly reported as a pathogen causing the cutaneous, subcutaneous or invasive infection. In this report, we present a case of cutaneous phaeohyphomycosis due to E. jeanselmei on the right hand of a farmer, who suffered from this disease three years ago which had not been definitely diagnosed until he was admitted to our hospital. In our hospital, a potential fungal pathogen was observed by histopathological examination, and then was recovered and identified as E. jeanselmei by sequencing its internal transcribed spacer region. After 4 weeks of antifungal treatment, his hand recovered very well. To investigate the in vitro susceptibility of E. jeanselmei isolates to antifungal agents and compare the characteristics of their related infections among immunocompetent and immunocompromised patients, we reviewed 84 cases published in PubMed database between 1980 and 2020.

Empiric antifungal therapy in patients with cutaneous and subcutaneous phaeohyphomycosis.

We encountered two cases of phaeohyphomycosis caused by Exophiala jeanselmei and E. oligosperma that were treated with fosravuconazole and terbinafine, respectively. Our cases were successfully treated with empiric therapy before the pathogen's species or antifungal sensitivity had been determined. We summarized 32 cases of cutaneous and subcutaneous phaeohyphomycosis caused by Exophiala species in Japan. The patients received antifungals, including itraconazole, terbinafine, voriconazole, and fosravuconazole, and the treatment success rates of these monotherapies were 77% (17/22), 67% (8/12), 100% (5/5), and 50% (1/2), respectively. Although the broad-spectrum azole antifungal itraconazole is the first choice for treatment, terbinafine at 125 mg/day might exert the same efficacy. Fosravuconazole is a novel broad-spectrum azole and a moderate inhibitor of Cyp3A4 that causes fewer drug interactions than itraconazole and voriconazole, indicating a promising drug for this disease.

Meanderella rijsii, a new opportunist in the fungal order Pleosporales.

Subcutaneous phaeohyphomycosis is an implantation disease caused by melanized fungi and affect both immunocompetent as well as immunocompromised individuals. Diagnosis and treatment require proper isolation and accurate identification of the causative pathogen. We isolated a novel fungus from a case of subcutaneous phaeohyphomycosis in an immunocompetent patient. The 56-year-old patient suffered from a slowly progressive swelling on the metatarsophalangeal join of the left food. The isolated fungus lacked sporulation and sequences of the ribosomal operon did not match with any known species. In a multi-locus phylogenetic analysis involving five markers, the fungus formed a unique lineage in the order Pleosporales, family Trematosphaeriaceae. A new genus, Meanderella and a new species, Meanderella rijsii are here proposed to accommodate the clinical isolate. Whole genome analysis of M. rijsii revealed a number of genes that can be linked to pathogenicity and virulence. Further studies are however needed to understand the role of each gene in the pathogenic process and to determine the origin of pathogenicity in the family of Trematosphaeriaceae.

A rare case of phaeohyphomycosis due to Phaeoacremonium krajdenii from Odisha.

A 45-year-old healthy woodcutter presented with a cystic swelling on the sole of the left great toe. Other than barefoot walking, there was no history of trauma or significant illness in the past. Fine needle aspirate showed yeast and hyphae on microscopy and culture grew black mould which was identified as Phaeoacremonium krajdenii species and genus confirmed by internal transcribed spacer sequencing. Aspiration of the lesion resulted in cure. Phaeoacremonium is a genus of fungi which are rare human pathogens, and herein we report a rare case of phaeohyphomycosis due to Phaeoacremonium krajdenii from the state of Odisha, India.

In vitro activities of 8 antifungal drugs against 126 clinical and environmental Exophiala isolates.

BACKGROUND: Exophiala is the main genus of black fungi comprising numerous opportunistic species. Data on antifungal susceptibility of Exophiala isolates are limited, while infections are potentially fatal. MATERIALS AND METHODS: In vitro activities of eight antifungal drugs (AMB, five azoles, two echinocandins) against 126 clinical (n = 76) and environmental (n = 47) isolates from around the world were investigated. E. oligosperma (n = 58), E. spinifera (n = 33), E. jeanselmei (n = 14) and E. xenobiotica (n = 21) were included in our dataset. RESULTS: The resulting MIC90 s of all strains were as follows, in increasing order: posaconazole 0.063 µg/ml, itraconazole 0.125 µg/ml, voriconazole and amphotericin B 1 µg/ml, isavuconazole 2 µg/ml, micafungin and caspofungin 4 µg/ml, and fluconazole 64 µg/ml. Posaconazole, itraconazole and micafungin were the drugs with the best overall activity against Exophiala species. Fluconazole could not be considered as a treatment choice. No significant difference could be found among antifungal drug activities between these four species, neither in clinical nor in environmental isolates. CONCLUSION: Antifungal susceptibility data for Exophiala spp. are crucial to improve the management of this occasionally fatal infection and the outcome of its treatment.